Project Summary Fetal Growth Restriction (FGR) complicates 5-10% of all pregnancies in the U.S.A and currently has no treatment. The majority of these cases are due to placental insufficiency and studies indicate that these babies are at high risk of developing obesity, diabetes and cardiovascular disease in adulthood. The long-term goal is to establish safe, efficacious and specific non-invasive placental gene transfer in order to establish potential treatment strategies for fetal growth restriction. The overall objective of this application is to develop a polymer- based nanoparticle that can be taken up by the human syncytium and result in transgene expression and allow tracking and targeting developments for non-placental injection of the nanoparticle. The rationale behind this proposal is that it is expected to make significant steps toward a specific delivery mechanism for therapy in the placenta and to broaden the knowledge by which substances are endocytosed by the syncytium of the placenta. To accomplish the objective of this application the candidate intends to pursue the following specific aims: Aim 1: Targeting nanoparticle delivery and transgene expression to the placental syncytiotrophoblast. We hypothesize that peptide conjugation and the incorporation of organ-specific microRNAs will aid placental nanoparticle uptake and reduce off-target transgene expression. We will utilize in vitro human and in vivo murine studies to investigate nanoparticle uptake, assess transgene expression and address any off-target effects following delivery into the maternal circulation. Aim 2: Placental therapy in models of pre-existing fetal growth restriction. We hypothesize that nanoparticle-mediated placental IGF-1 therapy will rectify impaired placental development and fetal growth in animal models of pre-existing fetal growth restriction. We will use the Enos-/- mouse strain and a Guinea pig model of maternal nutrition restriction to investigate effects of placental-specific therapy after the onset of fetal growth restriction as would be the scenario in human pregnancy until the ability to predict placental insufficiency is developed. The use of placentally-targeted therapeutics are highly innovative, challenging current paradigms for the management of fetal growth restriction and moving gene therapy beyond imaging, targeting, and destruction of unwanted cells. The proposed research is significant because development of a placental targeting system to allow preferential nanoparticle delivery from the maternal circulation to the syncytiotrophoblast is essential to move this technology forward. Ultimately such capabilities and knowledge has the potential to lead to the development of the first effective treatment for Fetal Growth Restriction.